Recent evidence shows that the immune repertoire against cancer recognizes differentiation antigens, and that these are the most prevalent antigens in human cancers. This class of antigen is expressed not only by a malignant cell, but by normal cells, specifically of the same lineage, or stage of differentiation within a lineage. It is not clear whether effective immune responses to these "self" antigens can be generated, and if this immunity can lead to tumor rejection. It is also unknown if these immune responses would lead to autoimmune disease. The goal of this project is to determine how immune responses against differentiation antigens can lead to tumor rejection, forming the basis for developing cancer vaccines. Immunity to melanoma is the most studied system in human cancer. Melanosomes are organelles of pigment cells, including melanoma and melanocytes. These organelles contain differentiation antigens which include the glycoproteins of the tyrosinase family. Melanosomal antigens are the dominant antigens that are recognized by the immune system on human melanoma. Mouse tumor models have been developed to investigate passive and active immunity against tyrosinase family proteins. The specific aims are: 1) to determine how the immune system responds to self (differentiation) antigens found on tumor cells; 2) to study how the immune system uses immune recognition to these differentiation antigens to induce tumor rejection; and 3) to identify the structural and cellular features of the tyrosinase family of proteins that make these the dominant antigens on melanoma.